Almost half of new cancer diagnoses in adults in the U.S. will be of three types: cancers of the lung, breast, and prostate. If significant progress is to be made in reducing total cancer incidence, it will be important to finds means of preventing these major tumors. Toward this end, basic scientists have identified a variety of genes in experimental systems that may be important in the etiology of these cancers. Concordantly, epidemiologists have identified environmental factors that are associated with increased cancer risk (e.g., smoking and lung cancer). In addition, statistical geneticists have shown that for a large number of malignancies, the risk of developing and surviving cancer is not uniformly distributed throughout the population. However, to date, it has been difficult to synthesize the results of these diverse studies. The objective of this project to determine the role individual genetic variation plays in modifying the risk of cancer imposed by environmental factors. The ultimate goal of such studies will be the identification of individuals with genetically determined cancer susceptibility. To perform these studies, we are conducting a hospital-based case-control study. The goal is to obtain 1000 cases of each of the above cancer sites and a collection of 1000 controls. The study is identifying new DNA-based variation in an extended collection of detoxification genes which may mediate the carcinogenic effects of exogenous and endogenous exposures. Once identified, tests for association of variation in candidate loci in cases when compared to sex-matched controls who are smokers and non-smokers will be conducted. Assessment of association dependent on case characteristics will be made. Using family history information obtained from each case and control reference individual, the patterns of cancer aggregation in families will be assessed. Finally, the relationship between aggregation within families and variation of candidate genes in the probands and their family members will be determined. GSTA1, GSTA4, GSTM1, GSTM2, GSTM3, GSTP1, GSTT1, GSTT2, mGST, EPHX1, and NQO1 have been examined in the lung cancer subset for DNA-based variants previously described in the literature, or obtained through data mining publicly available sequence data utilizing the SNPpipeline of the NCI's CGAP Genetic Annotation Initiative. To account for the possibility of population stratification, the population was genotyped using the PE-Biosystems AmpFlSTR Profiler Plus forensic panel of 10 high heterozygosity STR loci. These markers were used to adjust the comparisons for background genetic differences unrelated to disease/control status that could confound outcomes. A total of 1638 individuals, including 699 lung cancer cases and 939 controls, were examined. Prior to adjustment for population stratification, variants at four loci showed significant associations (p <0.05) within the subset of cases and controls with a history of smoking: GSTA4, GSTM3, GSTT1, and GSTT2, and all four loci retained significance following adjustment for genetic background differences. In a subset analysis restricted to smokers, and adjusted for genetic background, GSTA4 was observed to be significantly associated with lung cancer (p = 0.022). Among nonsmokers, (adjusted for genetic background) GSTT1 and GSTT2 were observed to be significantly associated with lung cancer with p values of 0.0341 and 0.0285, respectively. To investigate possible joint effects of genetic susceptibility and diet in lung cancer risk, 438 subjects with dietary information were further analyzed. Cluster analysis was performed using nutrient densities of the four dietary constituents (protein, carbohydrate, animal fat, and dietary fiber) to identify groups of persons with similar dietary patterns. On stratified analysis of 329 smokers, a healthy dietary pattern was significantly associated with a decrease lung cancer risk among GSTM1 null individuals OR=0.46 (0.21-1.01). A protective effect of healthy diet and genotype was observed among individuals who do not carry the homozygosity of GSTP1 OR=0.16 (0.05-0.58), when compared to those who were homozygous and had an unhealthy diet. These data suggest that dietary factors can influence the role of certain genes encoding metabolic enzymes in lung cancer risk. Without clarification of the complex correlations between dietary constituents, adjustments using dietary patterns (as defined by our studies) may be useful in elucidating the genuine effects of genetic polymorphisms on carcinogen metabolism.